6-51906246-G-A

Variant names:

• chr6-51906246-G-A
• rs140065359
• NM_138694.4:c.6777C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_138694.4(PKHD1):​c.6777C>T​(p.Phe2259Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,611,740 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (31 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.33
• Publications: 2 publications found

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 6-51906246-G-A is Benign according to our data. Variant chr6-51906246-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167484.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.6777C>T	p.Phe2259Phe	synonymous	Exon 41 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.6777C>T	p.Phe2259Phe	synonymous	Exon 41 of 61	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.6777C>T	p.Phe2259Phe	synonymous	Exon 41 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.6777C>T	p.Phe2259Phe	synonymous	Exon 41 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 700 AN: 152124 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00712

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00503 AC: 1262 AN: 250796 AF XY: 0.00466

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00687

Gnomad OTH exome AF: 0.00655

GnomAD4 exome AF: 0.00490 AC: 7146 AN: 1459498 Hom.: 31 Cov.: 28 AF XY: 0.00488 AC XY: 3547 AN XY: 726244

African (AFR) AF: 0.000479 AC: 16 AN: 33394

American (AMR) AF: 0.00269 AC: 120 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86214

European-Finnish (FIN) AF: 0.0143 AC: 762 AN: 53388

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00531 AC: 5891 AN: 1110104

Other (OTH) AF: 0.00415 AC: 250 AN: 60270

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152242 Hom.: 6 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74430

African (AFR) AF: 0.000577 AC: 24 AN: 41564

American (AMR) AF: 0.00131 AC: 20 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00715 AC: 486 AN: 67998

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00555 Hom.: 4

Bravo AF: 0.00288

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00595

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal recessive polycystic kidney disease (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.2
DANN	Benign	0.65
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140065359; hg19: chr6-51771044;